“Cartilage tissue engineering is a growing field because cartilage does not regenerate,” said Elizabeth Loboa, Ph.D., dean of the MU College of Engineering and a professor of bioengineering, in the August 22, 2017 news release.

“Because these tissues cannot renew themselves, bioreactors, or devices that support tissue and cell development, are used in many cartilage tissue engineering applications. Some studies suggest that microgravity bioreactors are ideal for the process to take place, while others show that bioreactors that mimic the hydrostatic pressure needed to produce cartilage might be more ideal. Our first-of-its-kind study was designed to test both theories.”

As MU College of Engineering wrote in the news release, “Using human adipose, or fat cells (hASC) obtained from women, Loboa and her team tested chondrogenic differentiation in bioreactors that simulated either microgravity or hydrostatic pressure, which is the pressure that is exerted by a fluid. Researchers found that cyclic hydrostatic pressure, which has been shown to be beneficial for cartilage formation, caused a threefold increase in cartilage production and resulted in stronger tissues. Microgravity, in turn, decreased chondrogenic differentiation.”

“Our study provides insight showing that mechanical loading plays a critical role during cartilage development,” Dr. Loboa said. “The study also shows that microgravity, which is experienced in space and is similar to patients on prolonged bed rest or those who are paralyzed, may inhibit cartilage and bone formation. Bioengineers and flight surgeons involved with astronauts’ health should consider this as they make decisions for regenerating cartilage in patients and during space travel.”

Dr. Loboa told OTW, “From an orthopedic surgeon’s standpoint, our study shows the benefits of physiological loading to stimulate chondrogenesis. So, if a patient is on prolonged bed rest with a broken leg and no mechanical loading is occurring at the fracture site, then chondrogenesis (cartilage formation) could be delayed or inhibited. In normal secondary fracture healing, cartilage usually forms at the fracture site and that cartilage is then replaced by bone through the process of endochondral ossification. So, if cartilage formation is inhibited and/or delayed, fracture healing could be compromised.”

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Is Fracture Healing in Space Problematic?

Tracey Romero • Mon, September 11th, 2017

A team of bioengineers led by the University of Missouri have been thinking a lot about what would happen if an astronaut broke a leg or injured a knee while in space. Can a fracture heal just as well in space as it would on Earth?

In a recent study, Elizabeth Loboa, Ph.D., dean of the College of Engineering at the university and her team that includes researchers from the University of North Carolina and North Carolina State found that the key to that answer is gravity or ‘mechanical loading’.

Mechanical loading or forces that stimulate cellular growth for development, is required for creating cartilage that is then turned to bone but little is known about how cartilage develops in the absence of gravity or mechanical loads.

According to their study findings, microgravity may actually inhibit cartilage formation, complicating the healing process for astronauts who experience a fracture while in space as well as for patients on bed rest or who are paralyzed due to trauma.

“Because these tissues cannot renew themselves, bioreactors, or devices that support tissue and cell development, are used in many cartilage tissue engineering applications. Some studies suggest that microgravity bioreactors are ideal for the process to take place, while others show that bioreactors that mimic the hydrostatic pressure needed to produce cartilage might be more ideal. Our first-of-its-kind study was designed to test both theories,” Loboa said in a release.

The process through which cartilage is developed is called chondrogenic differentiation. Using human adipose, or fat cells (hASC) obtained from women, Loboa and her team tested chondrogenic differentiation in bioreactors that simulated either microgravity or hydrostatic pressure, which is the pressure that is exerted by a fluid.

The results showed that cyclic hydrostatic pressure, which has been shown to be beneficial for cartilage formation, caused a threefold increase in cartilage production and resulted in stronger tissues. Microgravity, in turn, decreased chondrogenic differentiation.

“Our study provides insight showing that mechanical loading plays a critical role during cartilage development,” Loboa said. “The study also shows that microgravity, which is experienced in space and is similar to patients on prolonged bed rest or those who are paralyzed, may inhibit cartilage and bone formation.

How Motion Causes Cartilage to Resorb Leaking Liquid

Elizabeth Hofheinz, M.P.H., M.Ed. • Mon, November 2nd, 2015

David Burris, Ph.D., an assistant professor in the Mechanical Engineering Department at the University of Delaware, has found some answers to the question, “Why doesn’t cartilage deflate over the course of days, months or years?”

Working from the idea that the cartilage was able to reabsorb the fluid that leaks out when we’re stationary, Dr. Burris hypothesized that the reabsorption process was driven by hydrodynamic pressurization. As indicated in the October 12, 2015 news release, the researchers “placed oversized cartilage samples against a glass flat to ensure the presence of the necessary wedge. They found that at slow sliding speeds cartilage thinning and an increase in friction occurred over time, but as the sliding speed increased toward typical walking speeds, the effect was reversed.”

Dr. Burris told OTW, “From biphasic modeling, we know that cartilage loses fluid during loading over time, but in vivo measurements show that although this is true in static conditions, articulation actually drives fluid back into the tissue. The community has not understood this mechanism and given the importance of the fluid in the tissue for mechanical and biological function, we felt this was an absolutely critical scientific question to answer. To date the only hypotheses have been that migration limits time in contact and articulation exposes the contact to the bath, which enable it to imbibe fluid to recover. We were shocked to find the same recovery mechanism others observe in the natural joint in a contact that did not involve migration and bath exposure. The results suggest that hydrodynamic pressure develops during articulation, but instead of creating fluid films as described in biomechanics textbooks, these external pressures combat the exudation process associated with interstitial pressurization. We believe this ‘tribological rehydration’ mechanism is critical for sustaining joint function and health and can be leveraged to provide unprecedented control in cartilage studies while maintaining physiological fluid pressures.”

Asked what orthopedic surgeons should know about this work, Dr. Burris commented, “First, the results contradict the conventional wisdom that articulation causes wear. The mechanism we propose based on our results suggest that the mechanical intensity felt by the solid is far less when active than when inactive.

Predict Onset of OA With Fluid Flow

Elizabeth Hofheinz, M.P.H., M.Ed. • Sun, February 21st, 2016

If we can detect of changes in the flow of interstitial fluid in articular cartilage, then we may be able to pick up on the onset of osteoarthritis. This work, done by researchers from the University of Eastern Finland, is the Ph.D. study of Janne Mäkelä, M.Sc.

As indicated in the February 16, 2016 news release, this work “focused on structural and functional changes in articular cartilage at different stages of osteoarthritis. By using finite element modelling, the study combined structural data with functional data measured from articular cartilage samples. This enabled a detailed analysis of how individual structural components affect cartilage loading, and how this process changes in the development of osteoarthritis.”

“The study used microscopic and spectroscopic methods to analyse the structure of articular cartilage samples, enabling the creation of a detailed finite element model to replicate the data obtained by mechanical measurements. Finite element modelling was more sensitive method, compared to exclusively elastic mechanical analysis, in identifying functional changes in early osteoarthritis.”

“The study showed the flow of interstitial fluid to be associated with many osteoarthritis-induced structural changes. Damage to the solid parts of the cartilage enhances the fluid flow from the cartilage, weakening its stiffness under static loading. Increase in the fluid flow seems to be the first functional change indicative of osteoarthritis.”

Mäkelä told OTW, “The results of my work show how tremendously vulnerable tissue the articular cartilage is. We used anterior cruciate ligament transected rabbits in the early osteoarthritis model. After four weeks, the alterations were seen, not only in the transected, but also in the non-operated contralateral knees. Histological scoring, done visually from microscopic slides, was unable to determine whether the contralateral samples had degenerated. However, the computational methods showed the behavior of the tissue to have changed dramatically. These kinds of alterations are a pathway towards osteoarthritis.”

“Hopefully in the future surgeons can have an quantitative method to evaluate the condition of the tissue during surgical procedures. Possibly an arthroscopic indentation instrument. But rather than evaluating only the stiffness of cartilage, perhaps the tissue fluid flow could be a better indicator as it was seen to be a result of the osteoarthritis-induced structural changes.

Growing Bone Replicates Anatomical Structure

Elizabeth Hofheinz, M.P.H., M.Ed. • Thu, June 30th, 2016

A new technique developed by Gordana Vunjak-Novakovic, Ph.D., the Mikati Foundation Professor of Biomedical Engineering at Columbia Engineering and professor of medical sciences (in Medicine) at Columbia University, repairs large bone defects in the head and face by using lab-grown living bone, tailored to the patient and the defect being treated. According to the June 15, 2016 news release, “This is the first time researchers have grown living bone that precisely replicates the original anatomical structure, using autologous stem cells derived from a small sample of the recipient's fat.”

Dr. Vunjak-Novakovic told OTW, “The technology is to repair large bone defects in head and face by using lab-grown living bone, tailored to the patient and defect being treated. The bone is formed by the recipient’s own cells (obtained from a small fat aspirate), within a scaffold made from bone matrix, in a perfused bioreactor. The scaffold and bioreactor chamber are fabricated based on the images of the defect, to provide a perfect anatomical fit.

“The particular scaffold we use allows bone formation without the use of growth factors, and at the same time provides mechanical competence under loading, both of which are unique advantages for clinical application. We compared implantations of engineered bone and a scaffold, both tailored to anatomical shapes, and showed major advantages of using living bone. Our bones maintain their health by a constant remodeling—resorption of some of the old bone, and its replacement by the new bone. Interestingly, while both the bone and scaffold grafts were processed by the body, only the bone grafts had biological ability to drive synthesis of new bone.

“Finally, and unexpectedly, the lab-grown bone, when implanted, was gradually replaced by new bone formed by the body, this serving as a template for bone formation rather than as a definitive implant. This feature is what makes this implant ‘your own bone’ that will become an integral part of the native bone.”

Regarding future research, she noted, “Because bone regenerates more readily than many other tissues, we are much closer to clinical application of this technology than most other applications, which is another reason that we are diligently working towards clinical trials.

Lizard Tails Prompt Cartilage Study

Biloine W. Young • Tue, April 8th, 2014

Lizards are not cuddly creatures but they can do something humans cannot—grow cartilage. If a lizard loses its tail it can regrow another one. The new tail will not have any bones in it, but the regrown cartilage will be strong enough the support the new tail.

The lizard's ability to regenerate cartilage has grabbed the attention of researchers because scientists, so far, have been unable to successfully replicate this lizard cartilage-growing ability in humans.

Two of those researchers are Thomas Lozito, Ph.D. and Rocky Tuan, Ph.D. of the Center for Cellular and Molecular Engineering at the University of Pittsburgh. As reported by the Orthopaedic Research Society, Lozito explained, "We study lizard cartilage to understand how it is able to be maintained in such a robust state. We have identified several key molecules known to play roles in normal skeletal development that are turned on in unusual and interesting patterns during lizard tail cartilage growth. These molecules are responsible for the unique tissue properties of regenerated lizard cartilage."

Lozito noted that scientists’ attempts to engineer cartilage tissue in the lab, “often results in cartilage that eventually calcifies and is replaced by bone, ” he said. This, of course, is of little help for those who suffer from degenerative joint diseases, such as osteoarthritis.

The researchers plan to examine the properties of the regenerated lizard tail that make it conducive for cartilage growth. Lozito said, “We have evidence that lizard cells themselves are particularly primed for differentiating into cartilage and that lizard cartilage itself contains a population of stem cells that readily forms new cartilage in response to trauma. This is practically the opposite of what occurs following damage to human cartilage."

Lozito said the group’s goal is to “identify the signals and cellular properties underlying the regenerative power of lizard tail cartilage which will afford new insights into actual cartilage regeneration and potentially yield lizard-inspired therapeutics and treatments for human cartilage diseases."